The majority of human autoimmune diseases are characterized by female predominance. Although sex hormone influences have been suggested to explain this phenomenon, the mechanism remains unclear. In contrast to the role of hormones, it has been suggested, based on pilot data in primary biliary cirrhosis, that there is an elevation of monosomy X in autoimmune disease. Using peripheral white blood cells from women with systemic sclerosis (SSc), autoimmune thyroid disease (AITD), or healthy age-matched control women, we studied the presence of monosomy X rates using fluorescence in situ hybridization. We also performed dual-color fluorescence in situ hybridization analysis with a chromosome Y α-satellite probe to determine the presence of the Y chromosome in the monosomic cells. In subsets of patients and controls, we determined X monosomy rates in white blood cell subpopulations. The rates of monosomy X increased with age in all three populations. However, the rate of monosomy X was significantly higher in patients with SSc and AITD when compared with healthy women (6.2 ± 0.3% and 4.3 ± 0.3%, respectively, vs 2.9 ± 0.2% in healthy women, p < 0.0001 in both comparisons). Importantly, X monosomy rate was more frequent in peripheral T and B lymphocytes than in the other blood cell populations, and there was no evidence for the presence of male fetal microchimerism. These data highlight the thesis that chromosome instability is common to women with SSc and AITD and that haploinsufficiency for X-linked genes may be a critical factor for the female predominance of autoimmune diseases.

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Objective-To establish the frequency of connective tissue diseases (CTD) in a cohort of Italian patients with primary biliary cirrhosis (PBC) and to evaluate the availability of a marker for the early identification of the more common associated CTD. Methods-One hundred and seventy consecutive patients with histologically diagnosed PBC were screened for the presence of a CTD and/or Raynaud's phenomenon (RP). Patients were classified as having a CTD only if they fulfilled standardised criteria. Results-Forty seven patients had a CTD. The most common CTD was systemic sclerosis (SSc), found in 21 patients. RP was present in 54 patients, most of whom (n=39) had an associated CTD. The most prevalent autoantibodies included antinuclear antibodies (ANA) with anticentromere (ACA) and speckled patterns (34 and 33 patients, respectively) and extractable nuclear antigens (ENA, 27 patients). However, while the frequencies of ACA and ENA were significantly higher in patients with an associated CTD (p<0.0001 and p<0.005, respectively), no relationship was found for speckled ANA. ACA was the best predictor of a CTD in patients with PBC (odds ratio (OR) 24.5, 95% CI 5.5 to 108.8), followed by the presence of ENA (OR 23.9, 95% CI 5.6 to 101.0) and RP (OR 20.2, 95% CI 5.7 to 71.2). Conclusions-Using strict standardised classification criteria we have found that SSc is the most common CTD associated with PBC and that ACA and ENA are strong markers for an associated CTD in patients with PBC.

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